Direct Activation of Human Dendritic Cells by Particle-Bound but Not Soluble MHC Class II Ligand

Renato B Baleeiro,Peter Walden,Karl-Heinz Wiesmüller,José A Barbuto,Lars Dähne,Jürgen Lademann

doi:10.1371/journal.pone.0063039

Abstract

Dendritic cells (DCs) are key activators of cellular immune responses through their capacity to induce naïve T cells and sustained effector T cell responses. This capacity is a function of their superior efficiency of antigen presentation via MHC class I and class II molecules, and the expression of co-stimulatory cell surface molecules and cytokines. Maturation of DCs is induced by microbial factors via pattern recognition receptors such as Toll-like receptors, pro-inflammatory cytokines or cognate interaction with CD4+ T cells. Here we show that, unexpectedly, the PanDR helper T cell epitope PADRE, a generic T helper cell antigen presented by a large fraction of HLA-DR alleles, when delivered in particle-bound form induced maturation of human DCs. The DCs that received the particle-bound PADRE displayed all features of fully mature DCs, such as high expression of the co-stimulatory molecules CD80, CD86, CD83, the MHC-II molecule HLA-DR, secretion of high levels of the biologically active IL-12 (IL-12p70) and induction of vigorous proliferation of naïve CD4+ T cells. Furthermore, the maturation of DCs induced by particle-bound PADRE was shown to involve sphingosine kinase, calcium signaling from internal sources and downstream signaling through the MAP kinase and the p72syk pathways, and finally activation of the transcription factor NF-κB. Based on our findings, we propose that particle-bound PADRE may be used as a DC activator in DC-based vaccines.

Highlights

Dendritic cells (DCs) are the most efficient and most important antigen presenting cells (APCs) for T cell priming and induction of adaptive immune responses [1]
Particles with Pan HLA-DR epitopes (PADREs) alone were found to efficiently induce maturation of immature dendritic cells (iDCs). Such an effect was first evidenced by the expression of the DC activation marker CD83 and up-regulation of the co-stimulatory molecules CD80 and CD86, and MHC class II (Figure 1)
The results of the investigations described demonstrate that the MHC class II-binding pan-DR epitope PADRE, when administered in particle-bound form, acts directly on iDCs to induce their phenotypic and functional differentiation into mature DCs with potent T cell-stimulating capacity

Summary

Introduction

Dendritic cells (DCs) are the most efficient and most important antigen presenting cells (APCs) for T cell priming and induction of adaptive immune responses [1]. Fully mature DCs produce pro-inflammatory cytokines, in particular interleukin (IL)-12, which plays critical roles in the induction of efficient CD4+ T helper cell (Th) and sustained effector CD8+ T cell immune responses characterized by high interferon (IFN)-c production and cytotoxicity [7]. These changes enable DCs to induce effective adaptive immune responses. Particle-bound in contrast to soluble PADRE was discovered to induce phenotypic and functional differentiation of immature into fully mature DCs with strong T cell-stimulatory capacity

Methods

Results

Conclusion